Atherosclerotic coronary artery disease (CAD) is one of the leading causes of mortality in the United States. Multiple epidemiologic studies have shown plasma levels of certain lipoproteins and their associated apolipoprotein moieties to be highly correlated with increased risk for development of CAD (The Expert Panel, 1988, Arch. Int. Med. 148:36-69; Kottke et al, 1986, Mayo Clinic Proceedings 61:313-320; Hoefler et al, 1988, Arteriosclerosis 8:398-401). Specifically, increased concentrations of low density lipoprotein (LDL), apoB, and lipoprotein Lp(a) as well as decreased high-density lipoproteins (HDL) and apoAI concentrations, have been implicated as risk stratifiers for development of premature atherosclerotic disease (Gordon et al, 1981, Arch. Intern. Med. 141:1128-31; Castelli et al, 1977, Circulation 55:767-772; Kottke et al, supra; Hoefler et al, supra). Therapeutic modalities presently exist that enable appropriate modulation of LDL and HDL metabolism, but therapy has not been specifically directed toward transcriptional regulation of the apolipoproteins.
ApoB is the product of a 43 kb gene residing on chromosome 2, which is composed of 29 exons and 28 introns (Ludwig et al, 1987, DNA 6:363-372). Transcription occurs in liver and intestine to produce a 14.1 kb mRNA. Regulation of apoB gene expression is achieved through a unique RNA editing mechanism; nucleotide 6666 can undergo a C to U substitution resulting in formation of a stop codon at this location in the transcript (Powell et al, 1987, Cell 50:831-840; Chen et al, 1987, Science 238:363-366; Higuchi et al, 1988, Proc. Natl. Acad. Sci. USA 85:1772-1776). Therefore, a single transcript can produce two isoproteins of 512 and 250 kDa, designated apoB-100 and apoB-48 respectively. Regulation of apoB at the transcriptional level has been only recently investigated (Das et al, 1988, J. Biol. Chem. 263:11452-11458; Carlsson and Bjursell, 1989, Gene 77:113-121; Levy-Wilson and Fortier, 1989, J. Biol. Chem. 264:9891-9896).
However, a factor, element or domain which suppresses the transcription of apoB has not heretofore been known or described.